Rett syndrome (RS) is an X-linked dominant disorder, affecting predominantly females. Female patients with RS characteristically exhibit microcephaly, mental retardation, seizures, autistic features, and stereotyped hand-wringing movements. RS is caused by mutations in the MeCP2 gene, which codes for a methyl-CpG binding protein. The mechanism by which defects in MeCP2 lead to the neurological phenotype in RS is unknown. Recently three groups described mouse models for RS generated by gene targeting. These have involved deletion of either exon 3, exon 3 and 4, or introducing a truncating mutation in the C-terminal domain. In this Animal Core, we propose to generate additional transgenic "knockin" mouse models for RS, which harbor common mutations that are found in human patients. We have selected three such mutations: (a) T158M, a common human mis-sense mutation in the methyl-binding domain (MBD) ofMeCP2, (b) R270X, a common human non-sense (truncating) mutation, that has a severe phenotype, and (c) A140 V, a mis-sense mutation associated with a milder phenotype in males. Specific objectives for the Animal Core include: (1) Construction of appropriate targeting vectors to introduce these point mutations into ES cells (by homologous recombination). (2) Generation of chimeric mice with these specific ES cell clones, and breeding for germ-line transmission. (3) Providing investigators with appropriate mice for behavioral, physiologic, and histopathological studies.